Protein-folding chaperones predict structure-function relationships and cancer risk in BRCA1 mutation carriers

Brant Gracia, Patricia Montes, Angelica Maria Gutierrez, Banu Arun, Georgios Ioannis Karras

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Predicting the risk of cancer mutations is critical for early detection and prevention, but differences in allelic severity of human carriers confound risk predictions. Here, we elucidate protein folding as a cellular mechanism driving differences in mutation severity of tumor suppressor BRCA1. Using a high-throughput protein-protein interaction assay, we show that protein-folding chaperone binding patterns predict the pathogenicity of variants in the BRCA1 C-terminal (BRCT) domain. HSP70 selectively binds 94% of pathogenic BRCA1-BRCT variants, most of which engage HSP70 more than HSP90. Remarkably, the magnitude of HSP70 binding linearly correlates with loss of folding and function. We identify a prevalent class of human hypomorphic BRCA1 variants that bind moderately to chaperones and retain partial folding and function. Furthermore, chaperone binding signifies greater mutation penetrance and earlier cancer onset in the clinic. Our findings demonstrate the utility of chaperones as quantitative cellular biosensors of variant folding, phenotypic severity, and cancer risk.

Original languageEnglish (US)
Article number113803
JournalCell Reports
Volume43
Issue number2
DOIs
StatePublished - Feb 27 2024

Keywords

  • BRCA1
  • cancer
  • CP: Cancer
  • expressivity
  • genetic variation
  • HSP70
  • HSP90
  • hypomorphism
  • penetrance
  • protein-folding chaperones
  • variants of uncertain significance

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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